Treating Negative Symptoms in Schizophrenia: an Update

Abstract

Opinion StatementInterest in the negative symptoms of schizophrenia has increased rapidly over the last several decades, paralleling a growing interest in functional, in addition to clinical, recovery, and evidence underscoring the importance negative symptoms play in the former. Efforts continue to better define and measure negative symptoms, distinguish their impact from that of other symptom domains, and establish effective treatments as well as trials to assess these. Multiple interventions have been the subject of investigation, to date, including numerous pharmacological strategies, brain stimulation, and non-somatic approaches. Level and quality of evidence vary considerably, but to this point, no specific treatment can be recommended. This is particularly problematic for individuals burdened with negative symptoms in the face of mild or absent positive symptoms. Presently, clinicians will sometimes turn to interventions that are seen as more “benign” and in line with routine clinical practice. Strategies include use of atypical antipsychotics, ensuring the lowest possible antipsychotic dose that maintains control of positive symptoms (this can involve a shift from antipsychotic polypharmacy to monotherapy), possibly an antidepressant trial (given diagnostic uncertainty and the frequent use of these drugs in schizophrenia), and non-somatic interventions (e.g., cognitive behavioral therapy, CBT). The array and diversity of strategies currently under investigation highlight the lack of evidence-based treatments and our limited understanding regarding negative symptoms underlying etiology and pathophysiology. Their onset, which can precede the first psychotic break, also means that treatments are delayed. From this perspective, identification of biomarkers and/or endophenotypes permitting earlier diagnosis and intervention may serve to improve treatment efficacy as well as outcomes.

Healthcare resource use in schizophrenia, EuroSC findings

“…In previous reports, 41% of patients experienced two or more negative symptoms [41], while as many as 58% had at least one negative symptom [42]. The impact of negative symptoms on overall functional impairment is substantial and no specific treatment can be considered particularly effective against these symptoms, according to the evidence base summarised in a recent review [43]. Negative symptoms of schizophrenia may pose a particular burden to patients, due to their links to lower quality of life and reduced social contact – a recent study, which also used the EuroSC cohort, showed that social isolation in patients with schizophrenia is associated with poor psychosocial functioning and low quality of life (QoL) [21].…”

Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia

“…Motivational deficits in patients with schizophrenia are persistent, are prevalent from the earliest stages of the disease, and may uniquely predict outcomes beyond other symptoms . Across several neuropsychiatric disorders, including schizophrenia, amotivation is associated with abnormal functioning of frontal‐striatal circuits involving the dorsolateral prefrontal cortex, anterior cingulate cortex, and ventral striatum (VS) .…”

Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

“…Their therapeutic benefit is assumed to be related to the blockade of D 2 receptors in the ventral striatum (nucleus accumbens). On the other hand, these compounds are not efficacious against the negative symptoms which may even aggravate (Millan et al, 2014; Remington et al, 2016). These drugs also induce several serious side-effects, either due to their off-targets including H 1 , α 2 , muscarinic2 (M 2 ) receptor antagonist properties, or to chronic central D 2 receptor blockade.…”

“…The negative symptoms remain one of the most difficult challenges in the treatment of schizophrenia (Millan et al, 2014; Remington et al, 2016). Interestingly, neuropsychopharmacological analysis tends to dissociate various symptoms of schizophrenia which could have distinct etiology (Buckley et al, 2009).…”